Hydroxyethylene peptide isostere

Kath, J.C., DiRico, A.P., Gladue, R.P., Martin, W.H., McEhoy, E.B., Stock, I.A Tylaska, L,A and Zheng, D. (2004) The discovery of structurally novel CCRl antagonists derived from a hydroxyethylene peptide isostere template, Bioorganic Si Medicinal Chemistry Letters, 14, 2163-2167. 

Figure 14 Profiling of aspartyl protease activity, (a) Catalytic mechanism of aspartyl proteases that cleave peptide bonds via activation of a water molecule, (b) A hydroxyethylene dipeptide isostere-based probe binds tightly to the active site and gets covalently attached via UV irradiation.

This modification seems to mimic the presumed tetrahedral intermediate involved in the aspartyl protease-catalyzed hydrolysis of the peptide bond. A HIV-1 protease inhibitor containing a hydroxyethylene bond isostere has been prepared on solid phase [143]. A Boc-N-protected bromomethyl ketone was coupled to the resin-bound N-free Pro-Ile-Val tripeptide, and the keto function was reduced to an OH group with NaBH4.The peptide analogue was then elongated on the resin.This procedure allows rapid access to a variety of hydroxyethylamino peptide bond isosteres, and in good yield. 

Hydroxyethylene dipeptidc isosteres 35, which are of interest as transition state analogs, e.g., in renin inhibitors where they replace the scissile dipeptide unit (Leu-Val) of angiotensinogen, the natural substrate of renin, can be obtained from optically active acid 32 via iodolactoniza-tion in several steps. The synthesis of 32 is achieved using an Ireland - Claisen rearrangement as the key step which allows complete control of the three stereogenic centers44. For a stereocontrolled synthesis of peptide bond isosteres via Claisen rearrangements see also ref 448. 

In 2003, a new Sml2-mediated carbon carbon bond-forming reaction was reported by Skrydstrup for the direct synthesis of peptide mimics for evaluation as protease inhibitors.90 For example, the low-temperature coupling of 4-thiopyridyl ester 100, derived from Cbz-protected phenylalanine, with the dipeptide acrylamide 101 gave the peptide analogue 102 in a 61% yield (Scheme 7.43). Ketone 102 represents a ketomethylene isostere of the tetra-peptide Phe Gly Leu Phe. Ketomethylene isosteres and the corresponding reduced analogues, hydroxyethylene isosteres, represent important and pharmaceutically relevant classes of protease inhibitors.91,92... 

Carboxamides are usually converted to sulfonamides as illustrated by the synthesis of the hypoglycemic sulfonyl isostere of glybenclamide. " The isosteric replacements for peptidic bonds have been summarized by Spatola and by Fauchere. The most used and well-established modifications are iV-methylation configuration change (D-configuration at Ca) formation of a retroamide or an a-azapeptide use of aminoisobutyric or dehydroamino acids replacement of the amidic bond by an ester (depsipeptide), ketomethylene, hydroxyethylene or thio-amide functional group carba replacement of the amidic carbonyl and use of an olefinic double bond (Fig. 13.17). 

Most HIV-PR inhibitor designs have focused on transition state analogues, i.e. analogues based on the known sequences of peptide substrates, but with the scissile bond replaced by a peptide bond isostere. Among the most effective peptide bond isosteres introduced into HIV-PR inhibitors have been the hydroxyethylene and hydroxyethyl-amine moieties (Fig. 20.7), in both of which the isosteric hydroxyl group is thought to mimic the tetrahedral... 

The discovery of peptide-based substrate-mimicking HIVPI was directed towards the synthesis of substrate analogs in which the scissile bond was replaced by a non-cleavable isostere with tetrahedral geometry that could mimic the tetrahedral transition-state of the proteolytic reaction. Thus, several inhibitors with hydroxyethylene or hydroxyethylamine isostere replacement were prepared to bind with the enzyme as shown in Fig. 3a [31]. However, the clinical development of peptide-derived compounds was hindered by their poor pharmacokinetics, including low oral bioavailability, rapid excretion and complex (expensive) synthesis [44,45]. Therefore, recently more... 

All the US-FDA approved Pis except Tipranavir (7) are substrate-based peptidic inhibitors. These inhibitors were designed using the "transition state peptidomimetic principle, which means that in the inhibitors the hydrolyzable peptide linkage is replaced by a non-hydrolyzable transition-state isostere (Fig. 11a) [158]. A munber of such isosteres were studied including statin, norstatin, hydroxyethylene, reduced amide, hydroxyethylamine, hydroxyethyl urea, monoalcohol, diol and aminodiols (Fig. 11b) [158]. Various classes of inhibitors containing dihydroxyethylene transition state isosteres were extensively developed. As an alternative to the peptide-based approach penicillin-derived C2 symmetric compounds were also pursued. 

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